Novel 4-(Piperidin-4-yl)-1-hydroxypyrazoles as γ-Aminobutyric AcidA Receptor Ligands: Synthesis, Pharmacology, and Structure−Activity Relationships

A series of substituted 1-hydroxypyrazole analogues of the GABAA receptor partial agonist 5-(4-piperidyl)-3-isoxazolol (4-PIOL) have been synthesized and pharmacologically characterized. Several of the analogues displayed Ki in the low nanomolar range at the native GABAA receptors and potent antagonism of the α1β2γ2 receptor. It appears that several regions situated in proximity to the core of the orthosteric binding site of the GABAA receptor are able to accommodate large hydrophobic substituents.